8G9P

Tricomplex of RMC-4998, KRAS G12C, and CypA

Summary for 8G9P

• Entry DOI: 10.2210/pdb8g9p/pdb
• Descriptor: GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, small gtpase, cancer, tricomplex, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 78191.45

Authors

Tomlinson, A.C.A.,Saldajeno-Concar, M.,Knox, J.E.,Yano, J.K. (deposition date: 2023-02-21, release date: 2023-08-16, Last modification date: 2024-10-16)

Primary citation

Schulze, C.J.,Seamon, K.J.,Zhao, Y.,Yang, Y.C.,Cregg, J.,Kim, D.,Tomlinson, A.,Choy, T.J.,Wang, Z.,Sang, B.,Pourfarjam, Y.,Lucas, J.,Cuevas-Navarro, A.,Ayala-Santos, C.,Vides, A.,Li, C.,Marquez, A.,Zhong, M.,Vemulapalli, V.,Weller, C.,Gould, A.,Whalen, D.M.,Salvador, A.,Milin, A.,Saldajeno-Concar, M.,Dinglasan, N.,Chen, A.,Evans, J.,Knox, J.E.,Koltun, E.S.,Singh, M.,Nichols, R.,Wildes, D.,Gill, A.L.,Smith, J.A.M.,Lito, P.
Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.
Science, 381:794-799, 2023

PubMed Abstract: The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

PubMed: 37590355
DOI: 10.1126/science.adg9652

Experimental method

X-RAY DIFFRACTION (1.5 Å)